High-density Lipoprotein Cholesterol Subclasses Research Articles

HDL Cholesterol: Physiology, Pathophysiology, and Management

Numerous epidemiological studies have identified high-density lipoprotein cholesterol (HDL) to be an independent risk factor for coronary heart disease (CHD). HDL is an emerging therapeutic target that could rival the impact of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) on LDL and CHD risk reduction. HDL metabolism, HDL kinetics, the concentration of various HDL subclasses, and other genetic factors affecting HDL functionality may all contribute to the anti-atherogenic properties of HDL; thus, standard plasma measurement may not capture the full range of HDL effects. Algorithms have been suggested to treat low HDL levels in subgroups of patients; however, no formal HDL target goals or treatment guidelines have been implemented as there is a lack of strong clinical evidence to support effective pharmacologic therapy for primary risk reduction. Available therapies have a modest impact on serum HDL levels; however, emerging therapies could have a more significant influence.

Rationale and design of the TRANSFACT project phase I: A study to assess the effect of the two different dietary sources of trans fatty acids on cardiovascular risk factors in humans

Background Detrimental effects of consumption of industrial trans fatty acids (TFA) from partially hydrogenated vegetable oils (PHVO) on cardiovascular disease (CVD) risk factors are well documented. However, very little information is available on the effect of natural sources of TFA coming from milk fat, dairy products and ruminant meat. In fact, due to the naturally low level of TFA in milk fat, it is almost impossible to conduct a clinical trial with a limited number of subjects (< 200). Methodology To compare the effects of industrial and natural dietary sources of TFA, two specific test fats have been designed and produced. A substantial amount of milk fat (130 kg) enriched in TFA has been produced by modification of the cow's diet and selection of cows with the highest TFA content. The level obtained was approximately 4- to 7-fold higher than typically present in milk fat (∼ 20 instead of 3–6 g/100 g of total fatty acids). The control fat is composed of PHVO balanced in saturated fatty acids (lauric, myristic and palmitic). Both experimental fats contain about 20–22% of monounsaturated TFA and the volunteers' daily experimental fat intake (54 g), will represent about 12.0 g/day of TFA or 5.4% of the daily energy (based on 2000 kcal/day). These two test fats have been incorporated into food items and will be provided to 46 healthy subjects under a randomised, double blind, controlled, cross-over design. The primary outcome is high-density lipoprotein cholesterol (HDL-C), which is an independent risk factor for CVD. Other parameters such as low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), and HDL-C level and subclasses will be also to be evaluated. Conclusion We have shown that it is technically feasible to perform a clinical trial on the comparative effects of natural and industrial sources of TFA isomers on CVD risk factors. Results are expected by mid-2006.

Effect of L-Carnitine on the Serum Lipoproteins and HDL-C Subclasses in Hemodialysis Patients

Aims: Following carnitine administration a decrease in plasma levels of triglyceride (TG) and increase in total high-density lipoprotein cholesterol (HDL-C) has been reported. Our hypothesis was that it also improves the HDL₂/HDL₃ ratio, symptomatic intradialytic hypotension, and anemia in hemodialysis (HD) patients. Methods: Forty HD patients with a mean (± SD) age of 53 ± 13 years were treated with 500 mg/day carnitine taken orally for 2 months. Patients were used as their own controls (before treatment). Lipid and lipoproteins were determined by Alcyon Abbott autoanalyzer. HDL subclasses were measured by magnesium precipitation after fractionation with dextran sulfate. Hemoglobin, hematocrit and serum albumin were measured by standard methods. The results were analyzed by SPSS 11.05. Results: We found a significant decrease in serum TG (2.22 ± 0.99 vs. 1.93 ± 1.07 mmol/l, p < 0.01) and VLDL-C (0.93 ± 0.36 vs. 0.81 ± 0.34 mmol/l, p = 0.01) and a marked increase in HDL-C (0.9 ± 0.16 vs. 1.06 ± 0.24 mmol/l, p < 0.05), HDL₂-C (0.17 ± 0.06 vs. 0.27 ± 0.14 mmol/l, p < 0.05) and albumin (37 ± 4 vs. 42 ± 5 g/l, p = 0.01) levels. The serum levels of total cholesterol (4.61 ± 0.89 vs. 4.5 ± 0.95 mmol/l, p = 0.1), LDL-C (2.78 ± 0.85 vs. 2.6 ± 0.89 mmol/l, p > 0.05), HDL₃-C (0.73 ± 0.1 vs. 0.79 ± 0.17 mmol/l, p > 0.05), hemoglobin, hematocrit, and intradialytic blood pressure did not change after the treatment. Conclusion: Treatment with 500 mg/day carnitine taken orally for 2 months reduces serum levels of TG and VLDL-C, and increases HDL-C, HDL₂-C and albumin in HD patients.

Advanced Lipoprotein Testing Does Not Improve Identification of Subclinical Atherosclerosis in Young Adults: The Bogalusa Heart Study

The clinical value of advanced lipoprotein testing relative to traditional lipid testing remains controversial. To date, no studies have evaluated associations between advanced lipoprotein testing and subclinical atherosclerosis in healthy young adults. To determine whether advanced lipoprotein testing using vertical-spin density-gradient ultracentrifugation better predicts carotid intima-media thickness, a validated measure of subclinical atherosclerosis, than does traditional lipoprotein testing in asymptomatic young adults. Cross-sectional community-based study. Bogalusa, Louisiana. 311 randomly selected adults from the Bogalusa Heart Study who were 20 to 38 years of age. The authors performed advanced lipoprotein testing using vertical-spin density-gradient ultracentrifugation, traditional testing using enzymatic methods, and Friedewald formula estimation of low-density lipoprotein cholesterol levels. A certified reader blinded to lipoprotein results determined carotid intima-media thickness by B-mode ultrasonography. C-statistics from area under the receiver-operating characteristic curves (AUCs) derived from multivariable regression models were compared. Lipid values obtained with advanced lipoprotein testing did not predict carotid intima-media thickness better than traditionally measured lipid values in 236 participants for whom all data were available. A model using traditional lipoprotein measures (AUC, 0.754 [95% CI, 0.690 to 0.812]) did not differ significantly from a model using advanced lipoprotein measures (AUC, 0.779 [CI, 0.662 to 0.871]) for prediction of carotid intima-media thickness (P > 0.2). Subclass pattern of LDL, lipoprotein(a) cholesterol, intermediate-density lipoprotein cholesterol, high-density lipoprotein cholesterol subclasses, and very-low-density lipoprotein subclasses did not improve the performance of models for prediction of carotid intima-media thickness. The study was cross-sectional, cardiac events were not determined, and only 1 method of advanced lipoprotein testing was used. Advanced lipoprotein testing using vertical-spin density-gradient ultracentrifugation did not improve prediction of carotid intima-media thickness in young adults and may not be useful for assessing cardiovascular risk in this population.

Dietary fat intake determines the effect of a common polymorphism in the hepatic lipase gene promoter on high-density lipoprotein metabolism: evidence of a strong dose effect in this gene-nutrient interaction in the Framingham Study.

Gene-nutrient interactions affecting high-density lipoprotein cholesterol (HDL-C) concentrations may contribute to the interindividual variability of the cardiovascular disease risk associated with dietary fat intake. Hepatic lipase (HL) is a key determinant of HDL metabolism. Four polymorphisms in linkage disequilibrium have been identified in the HL gene (LIPC), defining what is known as the -514T allele. This allele has been associated with decreased HL activity and increased HDL-C concentrations. However, the effect is variable among populations. We have examined interaction effects between the -514(C/T) LIPC polymorphism, dietary fat, and HDL-related measures in 1020 men and 1110 women participating in the Framingham Study. We found a consistent and highly significant gene-nutrient interaction showing a strong dose-response effect. Thus, the T allele was associated with significantly greater HDL-C concentrations only in subjects consuming <30% of energy from fat (P<0.001). When total fat intake was > or =30% of energy, mean HDL-C concentrations were lowest among those with the TT genotype, and no differences were observed between CC and CT individuals. We found similar gene-nutrient interactions when the outcome variables were HDL2-C (P<0.001), large HDL subfraction (P<0.001), or HDL size (P=0.001). These interactions were seen for saturated and monounsaturated fat intakes (highly correlated with animal fat in this population), but not for polyunsaturated fat. Dietary fat intake modifies the effect of the -514(C/T) polymorphism on HDL-C concentrations and subclasses. Specifically, in the Framingham Study, TT subjects may have an impaired adaptation to higher animal fat diets that could result in higher cardiovascular risk.

The effect of 7-year infancy-onset dietary intervention on serum LDL and HDL cholesterol subclasses in healthy children: The prospective, randomised strip study

The oxidation of lipoproteins is thought to be an important early step in atherogenesis. The measurement of lipid peroxidation in low-density lipoprotein (LDL) challenged with Cu2+ has become a widespread test to determine the “susceptibility” of LDL to oxidation. The determination of lag time to oxidation is thought to be a measure of the total antioxidant capacity of the LDL. However, we and others have failed to observe any correlation between lag time and the LDL content of its major lipid antioxidant, α-tocopherol. In fact, several studies now suggest a pro-oxidant role for tocopherol under some conditions of LDL oxidation. In the present study we sought to determine if there was a relationship between Cu2+ reduction by LDL and kinetic parameters of LDL oxidation. LDL (0.3 mmol/l cholesterol, ∼0.1 mg protein/ml) was incubated at 30°C with 2 μM Cu2+ and the formation of conjugated dienes measured over a 4-h period. Using neocuproine, an indicator molecule that specifically complexes Cu+ but not Cu2+, the reduction of Cu2+ by LDL was monitored. The final Cu concentration in these assays was 100 μM and neocuproine 750 μM. Cu+ formation was measured by absorbance at 454 nm. A strong negative correlation was observed between copper reduction by LDL and lag time to oxidation (r = −0.66, p < .005, n = 16). Further experiments showed that (1) LDL was able to reduce Cu2+ to Cu+ in a time and concentration-dependent manner; (2) blocking of free —SH groups on LDL apoprotein B by preincubation with dithionitrobenzoic acid (DTNB) had no significant effect on the rate and extent of Cu2+ reduction; (3) consumption of tocopherol in LDL undergoing oxidation with Cu was very rapid (rate = 6 × 10−10 M s−1). When Cu+ formed during incubation with LDL was complexed with neocuproine, there was significant inhibition of LDL oxidation, as indicated by lipid peroxide formation and mobility on agarose gel electrophoresis. Surprisingly, tocopherol consumption was even more rapid in the presence of neocuproine, consistent with a shift in Cu2+/ Cu+ equilibrium and faster reduction of Cu2+ by α-tocopherol. These results indicate that under these conditions tocopherol is a major reducing agent in LDL, converting Cu2+ to Cu+, and therefore, may play an important role in promoting LDL oxidation. However, there was no correlation between LDL tocopherol content and reduction of Cu2+. Examination of the time course of Cu2+ reduction in tocopherol enriched and depleted LDL indicates that tocopherol may determine Cu reduction at early time points but that the eventual capacity of LDL to reduce Cu may depend on more complex interactions between tocopherol and other LDL components.

High-fiber oat cereal compared with wheat cereal consumption favorably alters LDL-cholesterol subclass and particle numbers in middle-aged and older men

No studies have examined whether increased consumption of oat cereal, rich in soluble fiber, favorably alters lipoprotein particle size and number. We examined the effects of large servings of either oat or wheat cereal on plasma lipids, lipoprotein subclasses, lipoprotein particle diameters, and LDL particle number. Thirty-six overweight men aged 50-75 y were randomly assigned to consume daily for 12 wk either oat or wheat cereal providing 14 g dietary fiber/d. Before and after the intervention, plasma lipid and lipoprotein subclasses were measured with proton nuclear magnetic resonance spectroscopy, and whole-body insulin sensitivity was estimated with the frequently sampled intravenous-glucose-tolerance test. Time-by-treatment interactions (P < 0.05) for LDL cholesterol (oat: -2.5%; wheat: 8.0%), small LDL cholesterol (oat: -17.3%; wheat: 60.4%), LDL particle number (oat: -5.0%; wheat: 14.2%), and LDL:HDL cholesterol (oat: -6.3%; wheat: 14.2%) were observed. Time-by-treatment interactions were nearly significant for total cholesterol (oat: -2.5%; wheat: 6.3%; P = 0.08), triacylglycerol (oat: -6.6%; wheat: 22.0%; P = 0.07), and VLDL triacylglycerol (oat: -7.6%; wheat: 2.7%; P = 0.08). No significant time-by-treatment interactions were observed for HDL cholesterol, HDL-cholesterol subclasses, or LDL, HDL, and VLDL particle diameters. Insulin sensitivity did not change significantly with either intervention. The oat compared with the wheat cereal produced lower concentrations of small, dense LDL cholesterol and LDL particle number without producing adverse changes in blood triacylglycerol or HDL-cholesterol concentrations. These beneficial alterations may contribute to the cardioprotective effect of oat fiber.

Diet and its relation to coronary heart disease.

Diet and its relation to coronary heart disease.